PROJECT SUMMARY Auditory neuropathy spectrum disorder (ANSD) is a neurological condition characterized by abnormal or nearly absent auditory brainstem responses despite normal otoacoustic emissions. Patients diagnosed with ANSD can have normal hearing thresholds, but have great difficulty localizing and understanding temporally complex sounds such as human speech. The peripheral etiology of ANSD is relatively well understood: degeneration of cochlear spiral ganglion neurons leads to dysfunctional auditory brainstem responses without affecting hair cell function. However, the most puzzling aspect of ANSD is that patients have normal cortical evoked potentials and can detect sounds at near normal levels despite the dramatic loss of brainstem evoked potentials. Recent findings suggest that this dichotomy may arise from a compensatory plasticity at higher stages of central processing. Studies using animal models of neuropathy have shown enhanced gain in the auditory cortex (ACtx) following cochlear denervation, and this additional amplification of weak afferent inputs may lead to the recovery of some aspects of sound processing in ACtx. This proposal will use anatomical and physiological methods to determine the time course and biological components of increased cortical amplification following peripheral denervation, using a mouse model of ANSD. We will use transcranial intrinsic signal imaging to track the recovery of auditory cortical activity in individual mice, following surgery to induce selective cochlear afferent denervation. At key stages of cortical recovery, we will identify transcriptional (Aim 1), anatomical (Aim 2) and physiological changes (Aim 3) in ACtx neurons that indicate a shift towards increased excitability. Finally, we will determine whether these shifts are specific to certain layers of auditory cortex, and specific to certain types of ACtx neurons. Our findings will reveal strategies that ACtx neurons use to compensate for lost afferent input and maintain behaviorally normal levels of sound perception.